Vascular endothelium, the inner lining of blood vessels, is crucially important to maintaining vascular health. Endothelial cells regulate thrombosis, inflammation, vasomotion, and cell proliferation through the synthesis and release of substances including nitric oxide and endothelin-1. Cardiovascular risk factors are associated with endothelial dysfunction, and agents that reduce cardiovascular risk also improve endothelial function. Hence, endothelial dysfunction is considered to be an important common pathway by which risk factors promote atherosclerosis. Furthermore, endothelial dysfunction is associated with coronary events. Consequently, there is much interest in assessing endothelial function noninvasively.
Vascular endothelial dysfunction also has been found to be the earliest detectable occurrence in the development of atherosclerosis. Function of the vascular endothelium is affected by various factors including the presence of various substances such as oxidized low-density lipoprotein and nitric oxide, or by physical stimuli. Therefore, assessment of vascular physiology is important in detecting and tracking the development of early stage atherosclerosis. Additionally, it will also be crucial to studies in inflammation, stroke, hypertension and diabetes research, as well as additional complications affected by atherosclerosis.
Arterial smooth muscle relaxation is mediated by endothelial dependent mechanisms (Furchgott R F, Zawadski J V. The obligatory role of endothelial cells in the relaxation of arterial smooth muscle by acetylcholine. Nature. 1980; 288:373.), which involve the release of nitric oxide (Palmer R, et al. Nitric oxide release accounts for the biologic activity of endothelium-derived relaxing factor. Nature. 1987; 327:524-526.). In vitro, the primary hemodynamic determinant of endothelial release of nitric oxide and subsequent vasodilation is wall shear stress (WSS) (Koller A, Kaley G. Endothelial regulation of wall shear stress and blood flow in skeletal muscle microcirculation. Am J Physiol. 1991; 260:H862-H868.; Koller A, et al. Role of shear stress and endothelial prostaglandins in flow- and viscosity-induced dilation of arterioles in vitro. Circ Res 1993; 72:1276-1284.; Busse R, et al. Signal transduction in endothelium-dependent vasodilation. Eur Heart J. 1993; 14:Suppl I, 2-9.; Busse R, Fleming I. Pulsatile stretch and shear stress: physical stimuli determining the production of endothelium-derived relaxing factors. Journal of Vascular Research. 1998; 35:73-84.) Larger increases in non-pulsatile shear stress have been shown to produce greater increases in diameter of isolated arteries from rat skeletal muscle (Koller A, Kaley G. Endothelial regulation of wall shear stress and blood flow in skeletal muscle microcirculation. Am J Physiol. 1991; 260:H862-H868.). However, the effects of pulsatile shear stress are different than those of constant shear stress (Ziegler T, et al. Influence of oscillatory and unidirectional flow environments on the expression of endothelin and nitric oxide synthase in cultured endothelial cells. Arterioscler Thromb Vasc Biol. 1998; 18:686-692.; Malek A M, et al. Modulation by pathophysiological stimuli of the shear stress-induced up-regulation of endothelial nitric oxide expression in endothelial cells. Neurosurgery. 1999; 45:334-344.).
In humans, reduced flow-mediated dilation (FMD) in hypertension has been found to result from at least in part lower baseline systolic wall shear stress (WSS) (Khder Y, et al. Shear stress abnormalities contribute to endothelial dysfunction in hypertension but not in type II diabetes. J Hypertens. 1998; 16:1619-1625.). Conversely, an increase in blood flow following a brief period of skeletal muscle ischemia is accompanied by dilation of the conduit artery (Sinoway Li et al. Characteristics of flow-mediated brachial artery vasodilation in human subjects. Circ Res. 1989; 64:32-42.; Celermajer D S, et al. Noninvasive detection of endothelial dysfunction in children and adults at risk of atherosclerosis. Lancet. 1992; 340: 1111.). Furthermore, increases in the magnitude or duration of hyperemia lead to increased vasodilation, while arterial diameter decreases during a low-flow state caused by distal arterial occlusion (Corretti M C, et al. Technical aspects of evaluating brachial artery vasodilation using high-frequency ultrasound. Am J Physiol. 1995; 268:H1397-H1404.; Leeson P, et al. Non-invasive measurement of endothelial function: effect on brachial artery dilation of graded endothelial dependent and independent stimuli. Heart. 1997; 78:22-27.). The relationship between WSS and arterial flow-mediated dilation (FMD) in humans was previously established (Silber H S, et al, The Relationship Between Vascular Wall Shear Stress and Flow-Mediated Dilation: Endothelial Function Assessed by Phase-Contrast Magnetic Resonance Angiography, JACC 2001; Vol. 38, No. 7; December 2001:1859-65).
Vascular physiology can be assessed, in part, through measurements of endothelial function. Changes in the diameter of an artery in response to a stimulus such as change in blood flow velocity through the artery (arterial wall shear stress, WSS) are indicative of endothelial function, known as flow mediated dilation (FMD). Endothelial function can be measured by inflating a blood pressure cuff around a subject's arm and monitoring velocity of blood flowing through a brachial artery while measuring the artery's diameter before, during and after the inflation of the cuff.
Ultrasound measurements of flow mediated dilation have been widely used to study endothelial function in patients with known cardiac risk factors with (Hoeks A P G, et al. Noninvasive determination of shear-rate distribution across the arterial lumen. Hypertension. 1995; 26:26-33.; Levine G N, et al. Ascorbic acid reverses endothelial vasomotor dysfunction in patients with coronary artery disease. Circulation. 1996; 93:210-214.; Vogel R A, et al. Changes in flow-mediated brachial artery vasoreactivity with lowering of desirable cholesterol levels in healthy middle-aged men. Am J. Cardiol. 1996; 77:37-40.; Motoyama T, et al. Endothelium-dependent vasodilation in the brachial artery is impaired in smokers: effect of vitamin C. Am J Physiol. 1997; 273:H1644-H1650.; Plotnick G D, et al. Effect of antioxidant vitamins on the transient impairment of endothelial-dependent brachial artery vasoactivity following a single high-fat meal. JAMA. 1997; 278:1682-1686.; Hornig B, et al. Vitamin C improves endothelial function of conduit arteries in patients with chronic heart failure. Circulation. 1998; 97:363-368.; Neunteufl T, et al. Additional benefit of vitamin E supplementation to simvastatin therapy on vasoreactivity of the brachial artery of hypercholesterolemic men. J Am Coll Cardiol. 1998; 32:711-716.; Chambers J C, et al. Demonstration of rapid onset vascular endothelial dysfunction after hyperhomocysteinemia: an effect reversible with vitamin C therapy. Circulation. 1999; 99:1156-1160.) and without (Celermajer D S, et al. Noninvasive detection of endothelial dysfunction in children and adults at risk of atherosclerosis. Lancet. 1992; 340:1111.; Celermajer D S, et al. Cigarette smoking is associated with dose-related and potentially reversible impairment of endothelium-dependent dilation in healthy young adults. Circulation. 1993; 88:2149-2155.; Celermajer D S, et al. Passive smoking and impaired endothelium-dependent arterial dilation in healthy young adults. N Engl J Med. 1996; 334:150-154.) intervention. However, there is considerable overlap in the arterial dilatory response between individuals with and without cardiac risk factors (Corretti M C, et al. Technical aspects of evaluating brachial artery vasodilation using high-frequency ultrasound. Am J Physiol. 1995; 268:H1397-H1404.; Celermajer D S, et al. Cigarette smoking is associated with dose-related and potentially reversible impairment of endothelium-dependent dilation in healthy young adults. Circulation. 1993; 88:2149-2155.; Celermajer D S, et al. Passive smoking and impaired endothelium-dependent arterial dilation in healthy young adults. N Engl J Med. 1996; 334:150-154.). This is in part because FMD is inversely related to baseline diameter (Celermajer D S, et al. Noninvasive detection of endothelial dysfunction in children and adults at risk of atherosclerosis. Lancet. 1992; 340:1111.). There is evidence from the study of rat skeletal muscle arterioles that this inverse relationship may be due to an inverse relationship between baseline diameter and wall shear stress (Koller A, Kaley G. Endothelial regulation of wall shear stress and blood flow in skeletal muscle microcirculation. Am J Physiol. 1991; 260:H862-H868.).
Current methods to assess endothelial function non-invasively use ultrasound to measure flow mediated dilation of a limb artery after release of a temporary occlusion of that limb. This method exploits the fact that shear stress is the primary hemodynamic stimulus of endothelial function, and that increased shear stress induces dilation in human peripheral arteries due primarily to nitric oxide release. However, use of ultrasound poses problems for assessment of vascular endothelial function. In addition to those technical problems discussed above wherein there is significant overlap of readings between patient populations, ultrasound measurements may be poorly reproducible because the technique is highly operator dependent with regard to probe positioning. Additionally, although dilation may be measured additional measurements to determine shear stress stimulus by ultrasound can only be accomplished using sophisticated, non-standard, signal processing equipment.
Conversely with hyperemia-induced dilation, decreased flow induces constriction of peripheral arteries. Low-flow mediated constriction is also endothelial-dependent, and is mediated by endothelin-1 via endothelin A receptors. However, low-flow mediated constriction has been studied much less extensively than flow mediated dilation. Furthermore, the relationship between the stimulus of shear reduction and the response of vasoconstriction has not been determined. In another method, phase contrast magnetic resonance imaging (PCMRI) is used to determine the relationship between flow mediated dilation and the hyperemic shear stimulus for flow mediated dilation.
It thus would be desirable to provide new non-invasive methods for assessing vasculature reactivity using magnetic resonance imaging as well as applications programs embodying such methods. It would be particularly desirable to provide such methods that would measure shear rate and/or vasculature dimensions. It also would be desirable to provide such methods in which such characteristics are measured during either of decreased or increased flow conditions as well as using techniques that user-independent.
The references discussed herein are provided solely for their disclosure prior to the filing date of the present application. Nothing herein is to be construed as an admission that the inventors are not entitled to antedate such disclosure by virtue of prior invention.